Project Summary/Abstract The prescription opioids crisis begs for a flexible but generalizable systems-level implementation strategy to widely improve prescribing practices. A consensus has emerged about safer prescribing practices, but determining how to implement needed changes remains a challenge. The proposed research will test an innovative way to implement that consensus, adaptive systems consultation. The research aims to identify which sequence and combination of implementation strategies works most effectively in promoting practice change in different primary care clinics. The research serves the long-term goal of learning how to optimize implementation strategies to promote evidence-based practice in primary care settings. This proposal builds on a pilot study that tested systems consultation in 4 primary care clinics, which found that systems consultation was feasible, acceptable, and effective in reducing patients? average opioid dose (an outcome directly related to the risk of overdose death). The proposed research tests an adaptive version of the strategy tailored to different levels (health system, clinic, prescriber). The intervention starts with academic detailing, a systems- level strategy consisting of an expert-led training session plus distance-based follow-up. This strategy continues for 18 months and serves as the control condition. At 3 months, half of the clinics will be randomized to receive practice facilitation, a clinic-level strategy aimed at improving processes related to opioid prescribing. At 6 months, prescribers will be assessed for guideline concordance, and half of non-guideline concordant prescribers will be randomized to receive physician peer coaching, a prescriber-level strategy, in which a physician expert gives one-on-one advice to prescribers in managing their patients on long-term opioid therapy. These 3 strategies will be delivered in a sequential, multiple-assignment randomized trial to 38 clinics from 3 Wisconsin health systems. The study compares the effect on average morphine milligram dose of an adaptive systems consultation implementation strategy (the intervention group) vs. academic detailing alone (the control group). The study will answer questions about the comparative effectiveness of prominent implementation strategies (academic detailing, practice facilitation, and physician peer coaching) in a single, highly efficient study. The study also develops an assessment of the contextual factors that influence the effectiveness of different implementation strategies and estimates the costs of delivering 4 different sequences and combinations of implementation strategies. This study will advance implementation science by testing a multi-level implementation strategy that can be tailored to assess contextual factors influencing implementation. This fundamental knowledge could be used to help mitigate the opioid crisis and in optimizing the selection and deployment of implementation strategies used to promote the uptake of many proven but underused practices throughout healthcare.